The present invention relates generally to compositions and methods for treating or preventing diseases of body passageways, and more specifically, to compositions comprising therapeutic agents which may be delivered to the external walls of body passageways.
There are many passageways within the body which allow the flow of essential materials. These include, for example, arteries and veins, the esophagus, stomach, small and large intestine, biliary tract, ureter, bladder, urethra, nasal passageways, trachea and other airways, and the male and female reproductive tract. Injury, various surgical procedures, or disease can result in the narrowing, weakening and/or obstruction of such body passageways, resulting in serious complications and/or even death.
For example, many types of tumors (both benign and malignant) can result in damage to the wall of a body passageway or obstruction of the lumen, thereby slowing or preventing the flow of materials through the passageway. In 1996 alone, it has been estimated that over 11,200 deaths will occur due to esophageal cancer, over 51,000 deaths due to large and small intestine cancer and nearly 17,000 deaths due to rectal cancer in the United States. Obstruction in body passageways that are affected by cancer are not only in and of themselves life-threatening, they also limit the quality of a patient""s life.
The primary treatment for the majority of tumors which cause neoplastic obstruction is surgical removal and/or chemotherapy, radiation therapy or laser therapy. Unfortunately, by the time a tumor causes an obstruction in a body passageway it is frequently inoperable and generally will not responded to traditional therapies. One approach to this problem has been the insertion of endoluminal stents. Briefly, stents are devices placed into the lumen of a body passageway to physically hold open a passageway that has been blocked by a tumor or other tissues/substances. Representative examples of commonly deployed stents include the Wallstent, Stecker stent, Gianturco stent and Palmaz stent (see e.g., U.S. Pat. Nos. 5,102,417, 5,195,984, 5,176,626, 5,147,370, 5,141,516, 4,776,337). A significant drawback however to the use of stents in neoplastic obstruction is that the tumor is often able to grow into the lumen through the interstices of the stent. In addition, the presence of a stent in the lumen can induce the ingrowth of reactive or inflammatory tissue (e.g., blood vessels, fibroblasts and white blood cells) onto the surface of the stent. If this ingrowth (composed of tumor cells and/or inflammatory cells) reaches the inner surface of the stent and compromises the lumen, the result is re-blockage of the body passageway which the stent was inserted to correct.
Other diseases, which although not neoplastic nevertheless involve proliferation, can likewise obstruct body passageways. For example, narrowing of the prostatic urethra due to benign prostatic hyperplasia is a serious problem affecting 60% of all men over the age of 60 years of age and 100% of all men over the age of 80 years of age. Present pharmacological treatments, such as 5-alphareductase inhibitors (e.g., Finasteride), or alpha-adrenergic blockers (e.g., Terazozan) are generally only effective in a limited population of patients.
Moreover, of the surgical procedures that can be performed (e.g., trans-urethral resection of the prostate (TURPs); open prostatectomy, or endo-urologic procedures such as laser prostatectomy, use of microwaves, hypothermia, cryosurgery or stenting), numerous complications such as bleeding, infection, incontinence, impotence, and recurrent disease, typically result.
In addition to neoplastic or proliferative diseases, other diseases such vascular disease can result in the narrowing, weakening and/or obstruction of body passageways. According to 1993 estimates (source-U.S. Heart and Stroke Foundation homepage), over 60 million Americans have one or more forms of cardiovascular disease. These diseases claimed 954,138 lives in the same year (41% of all deaths in the United States).
Balloon angioplasty (with or without stenting) is one of the most widely used treatments for vascular disease; other options such as laser angioplasty are also available. While this is the treatment of choice in many cases of severe narrowing of the vasculature, about one-third of patients undergoing balloon angioplasty (source Heart and Stoke Foundation homepage) have renewed narrowing of the treated arteries (restenosis) within 6 months of the initial procedure; often serious enough to necessitate further interventions.
Such vascular diseases (including for example, restenosis) are due at least in part to intimal thickening secondary to vascular smooth muscle cell (VSMC) migration, VSMC proliferation, and extra-cellular matrix deposition. Briefly, vascular endothelium acts as a nonthrombogenic surface over which blood can flow smoothly and as a barrier which separates the blood components from the tissues comprising the vessel wall. Endothelial cells also release heparin sulphate, prostacyclin, EDRF and other factors that inhibit platelet and white cell adhesion,VSMC contraction, VSMC migration and VSMC proliferation. Any loss or damage to the endothelium, such as occurs during balloon angioplasty, atherectomy, or stent insertion, can result in platelet adhesion, platelet aggregation and thrombus formation. Activated platelets can release substances that produce vasoconstriction (serotonin and thromboxane) and/or promote VSMC migration and proliferation (PDGF, epidermal growth factor, TGF-xcex2, and heparinase). Tissue factors released by the arteries stimulates clot formation resulting in a fibrin matrix into which smooth muscle cells can migrate and proliferate.
This cascade of events leads to the transformation of vascular smooth muscle cells from a contractile to a secretory phenotype. Angioplasty induced cell lysis and matrix destruction results in local release of basic fibroblast growth factor (bFGF) which in turn stimulates VSMC proliferation directly and indirectly through the induction of PDGF production. In addition to PDGF and bFGF, VSMC proliferation is also stimulated by platelet released EGF and insulin growth factor xe2x88x921.
Vascular smooth muscle cells are also induced to migrate into the media and intima of the vessel. This is enabled by release and activation of matrix metalloproteases which degrade a pathway for the VSMC through the extra-cellular matrix and internal elastic lamina of the vessel wall. After migration and proliferation the vascular smooth muscle cells then deposit an extra-cellular matrix consisting of gylcosaminoglycans, elastin and collagen which comprises the largest part of intimal thickening. A significant portion of the restenosis process may be due to remodeling of the vascular wall leading to changes in the overall size of the artery; at least some of which is secondary to proliferation within the adventitia (in addition to the media). The net result of these processes is a recurrence of the narrowing of the vascular wall which is often severe enough to require a repeat intervention.
In summary, virtually any forceful manipulation within the lumen of a blood vessel will damage or denude its endothelial lining. Thus, treatment options for vascular diseases themselves and for restenosis following therapeutic interventions continue to be major problems with respect to longterm outcomes for such conditions.
In addition to neoplastic obstructions and vascular disease, there are also a number of acute and chronic inflammatory diseases which result in obstructions of body passages. These include, for example, vasculitis, gastrointestinal tract diseases (e.g. Crohn""s disease, ulcerative colitis) and respiratory tract diseases (e.g. asthma, chronic obstructive pulmonary disease).
Each of these diseases can be treated, to varying degrees of success, with medications such as anti-inflammatories or immunosuppressants. Current regimens however are often ineffective at slowing the progression of disease, and can result in systemic toxicity and undesirable side effects. Surgcal procedures can also be utilized instead of or in addition to medication regimens. Such surgical procedures however have a high rate of local recurrence to due to scar formation, and can under certain conditions (e.g., through the use of balloon catheters), result in benign reactive overgrowth.
Other diseases that can also obstruct body passageways include infectious diseases. Briefly, there are a number of acute and chronic infectious processes that can result in the obstruction of body passageways including for example, urethritis, prostatitis and other diseases of the male reproductive tract, various diseases of the female reproductive tract, cystitis and urethritis (diseases of the urinary tract), chronic bronchitis, tuberculosis and other mycobacteria infections and other respiratory problems and certain cardiovascular diseases.
Such diseases are presently treated either by a variety of different therapeutic regimens and/or by surgical procedures. As above however, such therapeutic regimens have the difficulty of associated systemic toxicity that can result in undesired side effects. In addition, as discussed above surgical procedures can result in local recurrence due to scar formation, and in certain procedures (e.g., insertion of commercially available stents), may result in benign reactive overgrowth.
The existing treatments for the above diseases and conditions for the most part share the same limitations. The use of therapeutic agents have not resulted in the reversal of these conditions and whenever an intervention is used to treat the conditions, there is a risk to the patient as a result of the body""s response to the intervention. The present invention provides compositions and methods suitable for treating the conditions and diseases which are generally discussed above. These compositions and methods address the problems associated with the existing procedures, offer significant advantages when compared to existing procedures, and in addition, provide other, related advantages.
Briefly stated, the present invention provides methods for treating or preventing diseases associated with body passageways, comprising the step of delivering to an external portion of the body passageway a therapeutic agent. Within a related aspect, methods for treating or preventing diseases associated with body passageways are provided comprising the step of delivering to smooth muscle cells of said body passageway, via the adventia, a therapeutic agent. By delivering the therapeutic compound locally to the site of disease, systemic and unwanted side effects can be avoided and total dosages can potentially be reduced. Delivery quadrantically or circumferentially around diseased passageway also avoids many of the disadvantages of endoluminal manipulation, including damage to the epithelial lining of the tissue. For example damage to the endothelium can result in thrombosis, changes to laminar flow patterns, and/or a foreign body reaction to an endoluminal device, any of which can initiate the restenosis cascade. In the case of prostatic disease, avoiding instrumentation of the urethra can reduce the likelihood of strictures and preserve continence and potency.
A wide variety of therapeutic agents may be utilized within the scope of the present invention, including for example anti-angiogenic agents, anti-proliferative agents, anti-inflammatory agents, and antibiotics.
Within certain embodiments of the invention, the therapeutic agents may further comprise a carrier (either polymeric or non-polymeric), such as, for example, poly(ethylene-vinyl acetate) (40% crosslinked), copolymers of lactic acid and glycolic acid, poly (caprolactone), poly (lactic acid), copolymers of poly (lactic acid) and poly (caprolactone), gelatin, hyaluronic acid, collagen matrices, and albumen.
The therapeutic agents may be utilized to treat or prevent a wide variety of diseases, including for example, vascular diseases, neoplastic obstructions, inflammatory diseases and infectious diseases. Representative body passageways which may be treated include, for example, arteries, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, lacrimal ducts, the trachea, bronchi, bronchioles, nasal airways, eustachian tubes, the external auditory canal, uterus and fallopian tubes.
Within one particularly preferred embodiment of the invention, the therapeutic agent is delivered to an artery by direct injection via an outer wall of the artery into the adventia.
These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth below which describe in more detail certain procedures, devices or compositions, and are therefore incorporated by reference in their entirety.